The phenomenon of unidirectional noncross tolerance has been described for the analgesic comparison between morphine and etorphine. That is morphine pellet implanted mice tolerant to morphine analgesia were shown not to be tolerant to etorphine. Also the mice were not tolerant to heroin. The main factor responsible for this phenomenon is that the morphine pellet be left in place and not be removed before the analgesic effect to the challenging agents is measured. If the morphine pellet is removed, cross tolerance to etorphine was found. These findings are important because it is now possible to show that cross tolerance does not universally occur between different narcotic analgesics as would be assumed from the usual concept of narcotic tolerance. Part of the explanation of the unidirectional nontolerance appears to reside in the possibility that for the more hydrophilic narcotics like morphine, the blood brain barrier plays a role in the development of tolerance. This implication is derived from the finding that the morphine pelleted mice were not tolerant to intracerebral ventricullarly injected morphine (although they were highly tolerant to S.C. morphine). Thus, the research will be directed toward extending the unidirectional noncross tolerance phenomenon to the respiratory depressant and gastrointestinal motility inhibiting actions of the narcotic analgesics. The question is whether the phenomenon is unique to analgesia. Also, accessibility of the central nervous sites or respiratory depression should be different from those for analgesia when intracerebral ventricular injections are given.